PROJECT SUMMARY This R03 application requests funds for research in an area of high relevance to the mission of the NINDS; specifically, to use an existing mouse model of HIV-associated neurocognitive impairment (HIV-NCI) for preclinical testing of therapeutic vaccination to reverse the disease employing T cell vaccines against conserved determinants present on HIV worldwide. People living with HIV due to successful combination antiretroviral therapy CART have low HIV burdens, functioning immune systems, and are relatively healthy, but about half of them develop chronic HIV-NCI that is not currently treatable. The disease is believed to be driven by myeloid cell reservoirs of HIV that defy the CART- restored anti-HIV immune surveillance. This small grant application proposes to use our well- established model of HIV-NCI in conventional mice infected by chimeric HIV, EcoHIV, to test therapeutic vaccination against the disease using state of the art broadly specific mosaic Gag-Pol T cell vaccines created by our collaborator Dr. Tomas Hanke. As recently reported, HIV-NCI in EcoHIV infected mice can be reversed by intranasal insulin treatment, suggesting that neurons relevant to cognition remain viable despite HIV insult, consistent with spontaneous cognitive improvement seen in some patients with NCI. As shown in Preliminary Results, innate immune stimulation also reverses HIV NCI in infected mice, as well as reduces virus burdens, suggesting that infected cells can directly be controlled through immunological routes. Dr Hanke's previous T cell vaccines protect mice from EcoHIV infection, as shown in our collaboration. Importantly, the vaccines to be employed, presented as Gag-Pol mosaic constructs, carry globally conserved determinants that are also associated with low virus burden in human beings and have entered clinical evaluation. The overall goal of this proposal is to test the novel mosaic vaccines for their ability to affect virus burden and behavioral change in EcoHIV-infected mice with NCI. The Aim is a) to optimize responses to DNA-, replication-deficient poxvirus MVA-, and replication-deficient adenovirus-vectored vaccines for reduction of virus burden and recovery of learning and memory in HIV-NCI mice; and b) to begin to identify antigenic determinants recognized by T cells associated with protective responses. Methods include immunization routes, assessment of virus burden in various tissues, memory and learning tests, and assay of peptide responses of CD4 and CD8 T cells. This pilot study will form the basis of a comprehensive study to employ therapeutic vaccination to boost adaptive immune responses to globally shared HIV determinants to reverse or prevent the development of HIV cognitive disease in infected people.